Post-Chimeric Antigen Receptor T-Cell Therapy Hepatitis B Virus Reactivation After 23 Months of Entecavir Prophylaxis

ABSTRACT Hepatitis B virus (HBV) reactivation can occur in immunosuppressed patients. Specifically, HBV reactivation after chimeric antigen receptor T-cell (CAR T-cell) therapy is a known complication with few case reports and specific treatment guidelines. Our patient experienced HBV reactivation 27 months after CAR T-cell therapy even with 23 months of entecavir prophylaxis. This unique case highlights the need for further investigation into the risk of HBV reactivation after CAR T-cell therapy and the proper HBV prophylaxis during and after CAR T-cell therapy.


INTRODUCTION
Hepatitis B virus (HBV) reactivation is a known complication associated with immunosuppression. 1 In patients who develop acute HBV infection without subsequent chronic infection, reactivation may occur through immunosuppression or loss of immune control, through a rise in HBV DNA (over the patient's baseline or an absolute cutoff), or through reverse seroconversion from hepatitis B surface antigen (HBsAg) negative to positive, depending on the patient's HBsAg and total antibody to hepatitis B core antigen (anti-HBc) serology.Reactivated HBV can be categorized as HBV-associated hepatitis if alanine transaminase (ALT) increases by greater than or equal to 3 times the patient's baseline or .1005][6][7][8][9][10] Unfortunately, there have been few case reports describing HBV reactivation after CAR T-cell therapy, and limited safety analyses to help patients with HBV and providers understand the risks of CAR T-cell therapy.][5][6][7][8][9][10] Our case report demonstrates the risk of HBV reactivation after CAR T-cell therapy even with appropriate HBV prophylaxis.

CASE REPORT
The patient is a 72-year-old man with pertinent medical history of inactive HBsAg-negative/anti-HBc-positive HBV first diagnosed in 1990 and stage IV, high-grade (3A) follicular lymphoma diagnosed in 2015.

Background:
The patient received 8 cycles of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone; 1 cycle of obinutuzumab maintenance therapy; 2 cycles of rituximab, ifosfamide, carboplatin, and etoposide phosphate; and idelalisib therapy for his follicular lymphoma (Figure 2).Before, during, and after starting these treatment regimens, the patient Correspondence: Preethi G. Venkat, MD (hgn9ns@uvahealth.org).was HBsAg negative, anti-HBc positive, and had an undetectable HBV viral load.The patient was started on HBV prophylaxis with entecavir 0.5 mg daily 5 days before CAR T-cell therapy administration on April 26, 2021.Entecavir was discontinued in March 2023, 23 months after CAR T-cell therapy completion.A specialty pharmacy monitored the patient's compliance with entecavir via the patient's dispense history and phone calls with the patient until the medication was discontinued.As shown in Figure 3, aside from one small rise in aspartate aminotransferase (AST)/ALT directly after CAR T-cell administration, HBV and liver function test (LFT) laboratory test results remained stable during lymphoma treatments and at least 1 month after entecavir discontinuation.
Presentation: The patient presented to an outside facility in July 2023 for lethargy and was found to have AST/ALT in the 1,000s.His symptoms persisted, and at his oncology clinic visit the following week, he was found to have a total bilirubin of 8.1 mg/dL (conjugated 6.2), AST of 2,461 U/L, ALT of 2,083 U/ L, alkaline phosphatase of 290 IU/L, international normalized ratio (INR) of 1.5, and platelets of 209,000/mcL.This was 27 months after CAR T-cell therapy completion and 1 month after his computed tomography scan showing clinical remission.A liver ultrasound on the same day showed increased conspicuity of the portal triads reflecting nonspecific hepatitis.

DISCUSSION
Case studies have shown that with entecavir prophylaxis, patients with a history of HBV infection should generally be safe from HBV reactivation while undergoing CAR T-cell therapy.This is true for HBsAg-positive/anti-HBc-positive patients with case studies demonstrating no HBV reactivation while on prophylactic therapy. 10,13One case series did show reactivation, but only in 1 of 19 HBsAg-positive/anti-HBc-positive patients (5.3%) on entecavir prophylaxis. 3Case reports have also shown that patients with HBsAg-negative/anti-HBc-positive serologies have an incredibly low risk of HBV reactivation, even without HBV prophylaxis.In one study, very few HBsAgnegative/anti-HBc-positive patients (5.4%) undergoing CAR T-cell therapy were started on any infectious prophylaxis, and all patients avoided hepatitis B reactivation. 3rrent guidelines from the American Association for the Study of Liver Diseases (AASLD)state that HBsAg-negative, anti-HBc-positive patients should be started on prophylaxis for HBV when given treatments that target B lymphocytes, such as CAR T-cell therapy. 2 HBV prophylaxis should be started either as soon as possible before, or in conjunction with, the onset of immunosuppressive therapy and should be continued for 12 months afterward for patients undergoing anti-CD20 therapies.Entecavir has consistently been a preferred drug for HBV prophylaxis. 2At this time, no specific HBV prophylaxis guidelines have been tailored to address the myriad unique CAR T-cell therapy regimens such as the JCAR017 CAR T-cell therapy (B-lymphocyte, CD19-directed therapy) our patient received.
Interestingly, our HBsAg-negative/anti-HBc-positive patient was started on entecavir prophylaxis before starting CAR T-cell therapy and prophylaxis was continued for 23 months after therapy.Despite his low-risk serology and properly administered entecavir prophylaxis, our patient developed HBV reactivation and HBV-associated hepatitis.
5][16][17][18] Some studies have shown the potential for reducing the risk of HBV reactivation by administering an HBV vaccine before anti-Bcell therapies. 19The potential benefit in providing patients who are undergoing CAR T-cell therapy with an HBV vaccine remains unknown, but could be a promising option requiring further investigation, specifically for patients with pretherapy anti-HBs ,100 mIU/mL.
Our patient far exceeded the AASLD guidelines for HBV prophylaxis surrounding CAR T-cell therapy, but still developed HBV reactivation and HBV-associated hepatitis.This may be due to the presence of inactive CAR T cells that are prone to robust reactivation and transaminase elevation despite prophylaxis.An alternative explanation could be a very late HBV reactivation from a previous rituximab-containing therapy regimen where the patient did not receive HBV prophylaxis; however, the lengthy time course and normal HBV serologies and LFTs intervally before CAR T-cell therapy make this explanation less likely.
Our recommendation for patients with a history of HBV undergoing CAR T-cell therapy would be to measure LFTs every 3 to 6 months after discontinuation of prophylaxis, with prompt evaluation of HBV serologies following any changes in LFTs.This could expedite treatment for patients and potentially avoid complications of HBV reactivation.Further investigation is needed to understand the true risk for HBsAg-negative, anti-HBc-positive patients undergoing CAR T-cell therapy even with appropriate HBV prophylaxis.

Hospitalization:
On admission, laboratory test results showed a positive anti-HBc IgM and HBV viral load .48k.The patient was restarted on entecavir 0.5 mg daily.The patient's hepatic function was assessed daily, and he reached a peak INR of 1.7 and total bilirubin of 10.6 mg/dL.AST peaked at 3,462 U/L, and ALT peaked at 3,348 U/L.The patient denied herbal supplement use and was taking aspirin 81 mg and atorvastatin 40 mg daily at home.He originally contracted HBV in the Navy in 1990 and denied any high-risk behavior for HBV re-exposure before admission.The patient's physical examination was notable for mild jaundice, which was improved at discharge.The patient was seen outpatient a month after discharge with improved symptoms and an HBV viral load of 1,636 IU/mL, AST 51 U/L, and ALT 53 U/L.